3F8E

Coumarins are a novel class of suicide carbonic anhydrase inhibitors

Summary for 3F8E

• Entry DOI: 10.2210/pdb3f8e/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION, MERCURY (II) ION, ... (6 entities in total)
• Functional Keywords: carbonic anhydrase, inhibitors, disease mutation, lyase, metal-binding
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 30158.09

Authors

Temperini, C.,Maresca, A.,Scozzafava, A.,Supuran, C.T. (deposition date: 2008-11-12, release date: 2009-10-06, Last modification date: 2023-11-01)

Primary citation

Maresca, A.,Temperini, C.,Vu, H.,Pham, N.B.,Poulsen, S.-A.,Scozzafava, A.,Quinn, R.J.,Supuran, C.T.
Non-Zinc Mediated Inhibition of Carbonic Anhydrases: Coumarins Are a New Class of Suicide Inhibitors
J.Am.Chem.Soc., 131:3057-3062, 2009

PubMed Abstract: The X-ray crystal structure of the adduct between the zinc metalloenzyme carbonic anhydrase II (CA, EC 4.2.1.1) with the recently discovered natural product coumarin derivative 6-(1S-hydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one showed the coumarin hydrolysis product, a cis-2-hydroxy-cinnamic acid derivative, and not the parent coumarin, bound within the enzyme active site. The bound inhibitor exhibits an extended, two-arm conformation that effectively plugs the entrance to the enzyme active site with no interactions with the catalytically crucial zinc ion. The inhibitor is sandwiched between Phe131, with which it makes an edge-to-face stacking, and Asn67/Glu238sym, with which it makes several polar and hydrogen bonding interactions. This unusual binding mode, with no interactions between the inhibitor molecule and the active site metal ion is previously unobserved for this enzyme class and presents a new opportunity for future drug design campaigns to target a mode of inhibition that differs substantially from classical inhibitors such as the clinically used sulfonamides and sulfamates. Several structurally simple coumarin scaffolds were also shown to inhibit all 13 catalytically active mammalian CA isoforms, with inhibition constants ranging from nanomolar to millimolar. The inhibition is time dependent, with maximum inhibition being observed after 6 h.

PubMed: 19206230
DOI: 10.1021/ja809683v

Experimental method

X-RAY DIFFRACTION (2 Å)